Topical wound therapeutic compositions

ABSTRACT

There is provided a composition for healing burns and wounds in mammals, which contains a cromolyn compound or the combination of a cromolyn compound and hyaluronic acid a corticosteroid.  
     Advantageously, elements found in amniotic fluid are also included.

RELATED APPLICATION

[0001] This application is a continuation in-part of application Ser.No. 09/503,833 filed Feb. 15, 2000 of Lezdey et al.

BACKGROUND OF INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates the treatment of decubitus ulcers, burns,open sores, incisions and wounds in mammals. In particular, it relatesto topical wound therapeutic formulations containing a cromolyn compoundalone or the combination of hyaluronic acid (hyaluronan) and a cromolyncompound. The formulations can also be used in combination with elementsfound in amniotic fluid.

[0004] 2. Description of the Prior Art

[0005] Adult wound repair is characterized by fibrosis, scarring, andsometimes by contracture. The results of this deforming process affectevery form of surgery and can have devastating consequences. In contrastfetal wound healing proceeds without such fibrosis or scar formation,Michael T. Longaker, M.D., Ernie S. Chiu, B.S., N. Scott Adzick, M.D.,Michael Stern, D.D.S., Michael R. Harrison, M.D., and Robert Stern,M.D., Studies in Fetal Wound Healing, V. A Prolonged Presence ofHyaluronic Acid Characterizes Fetal Wound Fluid, Ann Surg, April 1991,pp. 292-296.

[0006] It is known that hyaluronic acid bonds with fibronectin andtogether they have a powerful effect on the body's cellular matrix. Itis also known that urea, produced by the fetus has an effect on cellmigration. Elements such as glucose, protein, sodium, potassium,calcium, magnesium, phosphate and chloride that form the amniotic fluid,work together with an inseparable bond and synergy.

[0007] Fibronectin is important in wound healing. However, the presenceof certain proteases in excess binds with the fibronectin and preventsits activity in healing.

[0008] Several prior art patents disclose therapeutic formulationsincluding hyaluronic acid. Lindblad, “Hyaluronic Acid Preparation usedfor Treating Inflammations of Skeletal Joints”; U.S. Pat. No. 4,801,619disclosed the use of hyaluronic for intra-articular administration forthe treatment of steroid arthropathy and progressive cartilagedegeneration caused by protoglycan degradation. Langerman, “Spare Partsfor Use in Ophthalmic Surgical Prodecures: U.S. Pat. No. 4,888,016disclosed the use of hyaluronic acid in ophthalmic surgery as anartificial “spare part” for surgical implantation in the eye during anextracapsular cataract extraction. Alvarez, “Three Step Wound TreatmentMethod and Dressing Therefor”; U.S. Pat. No. 4,813,924, which is hereinincorporated by reference, disclosed the use of hyaluronic acid in thethird step of a three-step treatment. The invention calls for hyaluronicacid to be in a hydrocolloid dressing which will provide controlleddelivery over a period of 24 to 96 hours to promote thickening of theepidermal cells, thus strengthening the wound. Balazs et al,“Cross-Linked Gels of Hyaluronic Acid and Products Containing SuchGels”; U.S. Pat. Nos. 4,582,865, 4,636,524 and 4,636,865 disclosed theuse of cross-linked gels of hyaluronic acid as a drug delivery system.

[0009] None of these prior art references claim to use hyaluronic acidand a cromolyn compound in the treatment of burns, open sores,incisions, and wounds and there is no combination with calcium,phosphate, uric acid, urea, sodium, potassium, chloride, and magnesiumto simulate amniotic fluid.

[0010] U.S. Pat. Nos. 5,190,917 and 5,290,762, which are hereinincorporated by reference disclose the roles of serine proteaseinhibitors in treatment of inflammation.

[0011] U.S. Pat. No. 4,970,298 which is herein incorporated by referencediscloses a biodegradable matrix which comprises collagen, hyaluronicacid and fibronectin which enhance healing of wounds. Collagen, which isoversecreted by the body in response to an injury or wound, is known tobe responsible for scar formation. Georgalas et al., “Skin TreatmentComposition and Method for Treating Burned Skin,” U. S. Pat. No.4,839,019, discloses a composition, which counteracts moisture loss andpromotes healing of burned or sunburned skin comprised ofpolyglycerylmethacrylate, glycerine, allantoin, panthenol, amino acidcomplex, and fibronectin.

BRIEF SUMMARY OF THE INVENTION

[0012] The invention relates to formulations containing a cromolyncompound selected from the group consisting of cromolyn, cromolynsodium, disodium cromolyn and esters thereof. There is also providedcombinations of a cromolyn compound and hyaluronic acid. The mixture canbe further combined with calcium, phosphate, uric acid, urea, sodium,potassium, chloride and magnesium, all elements found in amniotic fluid,to provide a unique synergy that is effective in the treatment of burns,open sores, incisions and wounds in mammals.

[0013] The invention is used for wound therapeutic formulations, fortopical application, for treating decubitus ulcers, burns, traumaticdamage caused by irradiation of the skin, the deleterious effects ofopen sores, incisions and wounds on skin and further provides a mixturewhich simulates the fetal in utero wound healing matrix in a safe andeffective amount.

[0014] Hyaluronic acid or the cromolyn compound alone in apharmaceutical base, are sufficient for treating minor injuries. Thecombination of a cromolyn compound and hyaluronic acid, speeds healing.Additional elements comprising a mixture of constituents selected fromthe group of calcium, phosphate, uric acid, urea, sodium, potassium,chloride and magnesium, which are found in amniotic fluid, promotehealing in more serious injuries.

[0015] The cromolyn compounds are inhibitors of PAR-2 (proteinaseactivator receptor-2) and prevent the degranulation of mast cells so asto control the release of chymase and tryptase that may cause scarring.

[0016] A preferred topical composition for use in serious injuries suchas burns comprises by weight of the mixture: 0.01% to 1.50% calcium;0.01% to 0.10% phosphate; 0.01% to 2.00% uric acid, 0.01% to 2.00% urea;0.02% to 1.50% sodium; 0.01% to 0.10% potassium; 0.01% to 0.70%chloride; 0.001% to 0.01% magnesium; 0.01% to 2.50% hyaluronic acid; and1.0% to 5.00% of a cromolyn compound.

[0017] In the best mode, the hyaluronic acid comprises by weight about0.10% to 2.50% of the mixture and the cromolyn compound about 1.0 to5.0% in the mixture or alone.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The invention is a means for delivery of cromolyn alone or thecombination of hyaluronic acid and a cromolyn compound in a topicalpreparation for the treatment of decubitus ulcers, burns, open sores,incisions and wounds for optimum healing.

[0019] In accordance with the invention, there is provided hereinformulations useful for topical application comprising a cromolyncompound alone or in combination with hyaluronic acid and/or at leastfour members of the group consisting of calcium, phosphate, uric acid,urea, sodium, potassium, chloride, and magnesium, all elements healingmatrix and a safe and effective amount of a topical carrier, incombinations described below.

[0020] Tissue repair in the mammalian fetus is fundamentally differentfrom normal adult healing. In adult humans, injured tissue is repairedby collagen deposition, collagen remodeling and eventual scar formation,whereas fetal wound healing appears to be more of a regenerative processwith minimal or no scar formation. The adult wound heals by thereplacement of normal dermis with a scar that consists of excessive andabnormally organized collagen. In marked contrast, the fetal woundcontains a persistent abundance of hyaluronic acid while collagendeposition is rapid and nonexcessive, Bruce A Mast, M.D., Robert F.Diegelmann, Ph.D., Healing in the Mammalian Fetus, Surg. Gyn. And Ob.,Vol. 174, pp. 441-451, May 92.

[0021] What is known is that hyaluronic acid has a definite role inharnessing and manipulating the natural reparative capacity of tissuefibroblasts and the hyaluronic acid protein complexes play a significantrole in vivo organization or scar tissue, D. A. R. Burd, R. M. Greco, S.Regaurer, M. T. Longaker, J. W. Siebert and H. G. Garg, Hyaluronan andWound Healing: a New Perspective, Journal of Plastic Sutery, 1991, pp.579-584.

[0022] Hyaluronic acid has played a very limited role in the care andtreatment of burns, open sores, incisions and wounds because there hasnot been an effective delivery system that could deliver hyaluronicacid, which is found in abundance in amniotic fluid, to the wound sitein a manner that replicated the moist environment and the other healingbenefits discovered in amniotic fluid.

[0023] It is understood that the term hyaluronic acid includes itsderivatives and broadly refers to naturally occurring, microbial andsynthetic derivatives of acidic polysaccharides of various molecularweights constituted by residues of glucuronic acid andN-acetyl-D-glucosamine.

[0024] The cromolyn compounds, because of their control of degranulationof mast cells and being anti-PAR-2, permit proper laying down of tissueand can prevent keloid scars. The serine protease inhibitor is used inan amount of about 0.5 to 5% by weight of the composition.

[0025] The wound healing process is significantly different in adults ascompared to the healing that takes place in amniotic fluid. Sharplyincreased levels of hyaluronic acid characterize adult wound healingduring the first three days. By the seventh day, hyaluronic acid is notdetectable.

[0026] Fetal wound healing is characterized by sharply increased levelsof hyaluronic acid during the first three days, but unlike adult woundhealing the level of hyaluronic acid remains elevated for 21 days. Thesefindings are the result of research conducted by Michael T. Longaker,M.D., Ernie R. Harrison, M.D., and Robert Stern, M.D. and reported in anarticle titled Studies in Fetal Wound Healing: V. A. Prolonged Presenceof Hyaluronic Acid Characterizes Fetal Wound Fluid, in Ann. Surg., April1991, pp. 292-296.

[0027] The healing process of the fetus is controlled by high levels ofhyaluronic acid and alpha 1-antitrypsin. In adult healing process thereis an overproduction of elastase which leads to the formation of scartissue. The topical addition of hyaluronic acid and a chymase andtryptase binding inhibitor in the wound bed will alter the adult healingprocess and facilitate accelerated healing and reduce the formation ofscar tissue. The presence of the cromolyn compound protects fibronectinfrom being degraded by elastase and other proteases.

[0028] Cell growth stimulating compound, may be incorporated into thecomposition. According to the present invention, the human growthhormone is utilized in an effective amount of at least about 0.05 ng/ml.Most preferably, the cell growth stimulating compound includes a mixtureof human growth hormone, insulin (containing transferrin ortransferrin-free) and/or triiodothyronine or thyroxin, each compound inan amount ranging from at least about 0.05 ng/ml, preferably at leastabout 0.5 ng/ml, and more preferably at least 1 ng/ml or more. In thecase of insulin, the effective amount of insulin generally ranges fromabout 5 ng/ml to about 100 ug/ml and more preferably about 50 ng/ml toabout 2 ug/ml within this range.

[0029] In addition to effective amount of cellular growth stimulatinghormone and cellular nutrient media, formulations according to thepresent invention may also contain hydrocortisone, which in certaininstances may have a beneficial overall effect in enhancing woundhealing.

[0030] Hydrocortisone is found to improve the cloning efficiency offibroblasts, enhancing the maintenance of epidermal keratinocytes. Thepreferred amount to be incorporated is generally within the range ofabout 0.2 umol to about 50 umol. The formulations according to thepresent invention may also include an effective amount of anantimicrobial agent, for example, antibiotics and antifungal agents,such as griseofulvin and nystatin and antiviral agents and the like. Theantimicrobial agent may be added for its ability to treat an infection,or alternatively, for its prophylactic effect in avoiding an infection.Cromolyn and hydrocortisone in the formulation are effective in treatingand/or preventing decubitus ulcers.

[0031] There are many different carriers, which can affectively guidedelivery to the skin. Such delivery system is desirable especially indogs who have the tendency to lick their wounds. Therefore, a liposomewhich causes a rapid infusion into the skin is desirable. One suchdelivery system is found in “Novasome” a trademark for a carrier ofEavsco Corp. of New Jersey.

[0032] Otherwise, an occlusive bandage type of carrier such as vasolineor aquaphor can be used.

EXAMPLE 1 A therapeutic skin lotion

[0033] A therapeutic skin lotion is prepared by combining the followingcomponents utilizing conventional mixing techniques. INGREDIENTPERCENTAGE BY WEIGHT Aloe Vera Gel 2.50% Tocopherol Acetate (Vitamin E)2.00% Glycerin 2.00% Stearic Acid 2.00% 1-Hexadecanol 2.00% Polysorbate60 2.00% Apricot Kernal Oil 2.00% Glyceryl Sterate 2.00% PEG-100Stearate 1.00% Cromolyn Sodium 5.00% Dimethicone 1.00% PVP 1.00%Hyaluronic Acid 0.50% Sodium 0.50% Allantoin 0.50% Triethanolamine 0.50%Carboner-940 0.20% Chloride 0.20% Potassium 0.05% Urea 0.06% Calcium0.05% Phosphate 0.03% Magnesium 0.01%

EXAMPLE 2 A Therapeutic Skin Gel

[0034] A therapeutic skin gel is prepared by combining the followingcomponents utilizing conventional mixing techniques. INGREDIENTPERCENTAGE BY WEIGHT Water 85.90% Aloe Vera extract 2.00% Glycerin 2.00%PVP 1.00% Triethanonmine 1.00% Sodium 0.70% Hyaluronic Acid 0.50%Disodium cromolyn 4.50% Allantoin 0.50% Carbomer-940 0.50% Chloride0.50% Potassium 0.05% Urea 0.06% Calcium 0.05% Phosphate 0.03% Magnesium0.01%

EXAMPLE 3

[0035] A formulation for the treatment of decubitus ulcers is preparedas follows: INGREDIENT PERCENTAGE BY WEIGHT Aquaphor ® 94.0% Cromolyn4.0% Hydrocortisone Acetate 0.5% Water 1.5%

EXAMPLE 4

[0036] Into Novasome of Eavsco Corp. is admixed 4.0% by weight ofcromolyn sodium 1.0% of hyaluronic acid and 0.5% hydrocortisone acetatefor use in treating hot spots on dogs.

[0037] Many alterations and modifications may be made by those havingordinary skill in the art without departing from the spirit and scope ofthe invention. Therefore, it must be understood that the illustratedembodiment has been set forth only for the purposes of example and thatit should not be taken as limiting the invention as defined by thefollowing claims. The following claims are, therefore, to be read toinclude not only the combination of elements which are literally setforth, but all equivalent elements for performing substantially the samefunction in substantially the same way to obtain substantially the sameresult. The claims are thus to be understood to include what isspecifically illustrated and described above, what is conceptionallyequivalent, and also what essentially incorporates the essence of theinvention.

1. A composition for topically treating decubitus ulcers, burns, opensores, incisions and wounds in mammals which comprises an effectiveamount of a cromolyn compound alone or in combination with an effectiveamount of hyaluronic acid in a suitable carrier.
 2. The composition ofclaim 1 wherein said carrier comprises a liposome.
 3. The composition ofclaim 1 including a corticosteroid.
 4. The composition of claim 1wherein said cromolyn compound is selected from the group consisting ofcromolyn sodium and disodium cromolyn.
 5. The composition of claim 4including amniotic fluid components.
 6. A substantially collagen-freecomposition for the treatment of decubitus ulcers, chronic burns, opensores, incisions and wounds in mammals composition comprising: About0.01 to 5% by weight of Hyaluronic acid; about 1.0 to 5.0% by weight ofcromolyn sodium; and a topical solution comprising a mixture of four ormore constituents selected from the group consisting of calcium,phosphate, uric acid, urea, sodium, potassium, chloride and magnesium.7. The composition of claim 6 including a corticosteroid.
 8. Thecomposition of claim 6 wherein said topical solution comprises by weightof said mixture: 0.01% to 1.50% calcium; 0.01% to 0.10% phosphate; 0.01%to 2.00% uric acid; 0.01% to 2.00% urea; 0.02% to 1.50% sodium; 0.01% to0.10% potassium; 0.01% to 0.70% chloride; and 0.001% to 0.01% magnesium.9. A method for treating burns, open sores, incisions and wounds formammals, which, comprises topically applying the composition of claim
 1. 10. A method for treating burns, open sores, incisions and wounds formammals, which, comprises topically applying the composition of claim
 3. 11. A method for treating burns, open sores, incisions and wounds formammals, which, comprises topically applying the composition of claim
 4. 12. A method for treating burns, open sores, incisions and wounds formammals, which, comprises topically applying the composition of claim 5.